MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes1,2, and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction3,4,5. Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy6,7. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells8. Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.
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Gene Expression Omnibus
Gene expression data have been deposited in the Genome Expression Omnibus under accession number GSE61851.
We thank M. Bosenberg, Y. Dang, A. Karabadzhak, and J. Zhou for discussions and suggestions; R. Ardito, M. Bonk, K. Card, D. Caruso, D. Jenci, D. Laliberte, W. Nazzaro, N. Santiago, and S. Wilson for rodent services; A. Brooks for tissue pathology services; Antech Diagnostics for complete blood count analysis; E. Aronesty, B. Cooper, and E. Norris at Expression Analysis for RNA-seq services; and J. Deacon, A. Kasinski, J. Sawyer, and C. Stahlhut for reading the manuscript. C.J.C. is the recipient of a Ruth L. Kirschstein Postdoctoral Fellowship from the National Cancer Institute/National Institutes of Health (NCI/NIH) (F32CA174247). Our work has been supported by grants from the NCI/NIH (R01CA131301), the National Heart, Lung, and Blood Institute (NHLBI)/NIH (R01HL085416), the National Institute of General Medical Sciences (NIGMS)/NIH (R01GM073857), the National Institute of Environmental Health Sciences (NIEHS)/NIH (R01ES005775), the NCI/NIH (R01CA148996), the National Institute of Biomedical Imaging and Bioengineering (NIBIB)/NIH (R01EB000487), the NHLBI/NIH (2T32HL007974), and pilot grants from the Yale Comprehensive Cancer Center.
Extended data figures
Mouse with hind limb paresis before pHLIP-anti155 treatment.
Four days after initiating IV administration of pHLIP-anti155 (two injections of 2 mg/kg spaced 2 days apart), paresis in the mouse is alleviated.
Additional mouse with hind limb paresis before pHLIP-anti155 treatment.
Four days after initiating IV administration of pHLIP-anti155 (one injection of 2.5 mg/kg), the mouse from Supplementary Video 3 has improved posture and gait.